Polymorphic form of [5-fluoro-3-({2-[(4-fluorobenzene) sulfonyl] pyridin-3-yl}methyl)-2-methylindol-1-yl]-acetic acid

ABSTRACT

The invention relates to a polymorphic form of [5-fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-acetic acid which has higher solubility than other forms and is therefore useful for preparing stable pharmaceutical formulations.

The present invention relates to a novel polymorphic form of a compoundwhich is useful as a pharmaceutical, to methods for preparing thispolymorph, compositions containing it and its use in the treatment andprevention of allergic diseases such as asthma, allergic rhinitis andatopic dermatitis and other inflammatory diseases mediated byprostaglandin D₂ (PGD₂) or other agonists acting at the CRTH2 receptoron cells including eosinophils, basophils and Th2 lymphocytes.

PGD₂ is an eicosanoid, a class of chemical mediator synthesised by cellsin response to local tissue damage, normal stimuli or hormonal stimulior via cellular activation pathways. Eicosanoids bind to specific cellsurface receptors on a wide variety of tissues throughout the body andmediate various effects in these tissues. PGD₂ is known to be producedby mast cells, macrophages and Th2 lymphocytes and has been detected inhigh concentrations in the airways of asthmatic patients challenged withantigen (Murray et al., (1986), N. Engl. J. Med. 315: 800-804).Instillation of PGD₂ into airways can provoke many features of theasthmatic response including bronchoconstriction (Hardy et al., (1984)N. Engl. J. Med. 311: 209-213; Sampson et al., (1997) Thorax 52:513-518) and eosinophil accumulation (Emery et al., (1989) J. Appl.Physiol. 67: 959-962).

The potential of exogenously applied PGD₂ to induce inflammatoryresponses has been confirmed by the use of transgenic miceoverexpressing human PGD₂ synthase which exhibit exaggeratedeosinophilic lung inflammation and Th2 cytokine production in responseto antigen (Fujitani et al., (2002) J. Immunol. 168: 443-449).

The first receptor specific for PGD₂ to be discovered was the DPreceptor which is linked to elevation of the intracellular levels ofcAMP. However, PGD₂ is thought to mediate much of its proinflammatoryactivity through interaction with a G protein-coupled receptor termedCRTH2 (chemoattractant receptor-homologous molecule expressed on Th2cells) which is expressed by Th2 lymphocytes, eosinophils and basophils(Hirai et al., (2001) J. Exp. Med. 193: 255-261, and EP0851030 andEP-A-1211513 and Bauer et al., EP-A-1170594). It seems clear that theeffect of PGD₂ on the activation of Th2 lymphocytes and eosinophils ismediated through CRTH2 since the selective CRTH2 agonists 13,14dihydro-15-keto-PGD₂ (DK-PGD₂) and 15R-methyl-PGD₂ can elicit thisresponse and the effects of PGD₂ are blocked by an anti-CRTH2 antibody(Hirai et al., 2001; Monneret et al., (2003) J. Pharmacol. Exp. Ther.304: 349-355). In contrast, the selective DP agonist BW245C does notpromote migration of Th2 lymphocytes or eosinophils (Hirai et al., 2001;Gervais et al., (2001) J. Allergy Clin. Immunol. 108: 982-988). Based onthis evidence, antagonising PGD₂ at the CRTH2 receptor is an attractiveapproach to treat the inflammatory component of Th2-dependent allergicdiseases such as asthma, allergic rhinitis and atopic dermatitis.

EP-A-1170594 suggests that the method to which it relates can be used toidentify compounds which are of use in the treatment of allergic asthma,atopic dermatitis, allergic rhinitis, autoimmune, reperfusion injury anda number of inflammatory conditions, all of which are mediated by theaction of PGD₂ or other agonists at the CRTH2 receptor.

Since the publication of EP-A-1170594, there have been a great manypublications relating to compounds having CRTH2 antagonist activity.

In our earlier applications WO-A-2005/044260, WO2006/095183 andWO2008/012511 we describe compounds which are antagonists of PGD₂ at theCRTH2 receptor. These compounds are indole-1-acetic acid derivativessubstituted at the 3-position with a CH2-aryl group which may besubstituted with one or more further substituents. The compoundsdescribed in these documents are potent antagonists in vitro of PGD₂ atthe CRTH2 receptor.

Our earlier application WO2009/090414 relates to pyridyl analogues ofthe compounds of WO2008/012511. Surprisingly, it has been found thatspecific pyridyl regioisomers and substitution thereof give rise to anoptimal balance of potency and pharmacokinetic properties. Specificallyit has been found that the introduction of a phenyl sulfonyl substituentonto the 2-position of the pyridin-3-yl regioisomer provides compoundswith good potency in a functional in vitro assay together with goodpharmacokinetics in vivo.

The compounds described in WO2009/090414 are, as predicted, useful inthe treatment of diseases and conditions mediated by the action of PGD₂at the CRTH2 receptor. One of these compounds,[5-fluoro-3-({2-[(4-fluorobnzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-aceticacid (Compound 1) is particularly useful.

A method for the synthesis of[5-fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-aceticacid is set out in WO2009/090414 but the present inventors found thatbatches of compound produced by this method are amorphous.

Crystalline forms are often more stable than amorphous forms and so anamorphous form may spontaneously convert to a crystalline form overtime. This is clearly a disadvantage in the case of pharmaceuticallyactive compounds as different forms of a compound may have differentpharmacokinetic properties. Therefore, the inventors set out to developa crystalline form of Compound 1.

The inventors also sought to prepare a crystalline form of anon-solvated form of Compound 1. Non-solvated forms are often moresuitable for the preparation of pharmaceutical compositions as manysolvates are thermodynamically unstable at ambient temperature, althoughhydrates are generally preferred to other solvates.

[5-fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-aceticacid was found by the present inventors to be enantiotropic and thus thestable polymorphic form of the compound depends upon the temperature.The inventors found three different polymorphic forms of this compound:a first, designated Form 1, which is thermodynamically stable at hightemperatures, although the exact transition temperature was difficult todetermine; a second (designated Form 2) which is thermodynamicallystable at temperatures up to about 60-65° C.; and a third form (Form 3)which is stable at temperatures between the stability ranges of Forms 2and 1.

The third polymorphic form, although not the most thermodynamicallystable form at room temperature and has the advantage of having a highersolubility than Form 1 and Form 2 It is therefore an highly advantageousform of Compound 1.

Therefore, in a first aspect of the present invention, there is provideda polymorphic form of[5-fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-aceticacid (Compound 1), characterised in that it gives an FT-Raman spectrumwhich is characterised by peaks at 3068±2 cm⁻¹, 3054±2 cm⁻¹, 2976±2cm⁻¹, 1582±2 cm⁻¹, 1427±2 cm⁻¹, 1298±2 cm⁻¹, 1213±2 cm⁻¹, 1190±2 cm⁻¹,1164±2 cm⁻¹, 1060±2 cm⁻¹, 956±2 cm⁻¹, 927±2 cm⁻¹, 834±2 cm⁻¹, 700±2cm⁻¹, 502±2 cm⁻¹, 421±2 cm⁻¹, 401±2 cm⁻¹, 388±2 cm⁻¹, 363±2 cm⁻¹, 353±2cm⁻¹, 301±2 cm⁻¹, 208±2 cm⁻¹, 116±2 cm⁻¹.

The complete Raman spectrum for Polymorphic Form 3 of Compound 1 ischaracterised by peaks at 3086±2 cm⁻¹, 3068±2 cm⁻¹, 3054±2 cm⁻¹, 2976±2cm⁻¹, 2940±2 cm⁻¹, 2919±2 cm⁻¹, 2757±2 cm⁻¹, 1629±2 cm⁻¹, 1582±2 cm⁻¹,1571±2 cm⁻¹, 1485±2 cm⁻¹, 1463±2 cm⁻¹, 1451±2 cm⁻¹, 1427±2 cm⁻¹, 1384±2cm⁻¹, 1355±2 cm⁻¹, 1311±2 cm⁻¹, 1298±2 cm⁻¹, 1213±2 cm⁻¹, 1190±2 cm⁻¹,1164±2 cm⁻¹, 1152±2 cm⁻¹, 1131±2 cm⁻¹, 1094±2 cm⁻¹, 1060±2 cm⁻¹, 1021±2cm⁻¹, 956±2 cm⁻¹, 927±2 cm⁻¹, 908±2 cm⁻¹, 882±2 cm⁻¹, 834±2 cm⁻¹, 824±2cm⁻¹, 773±2 cm⁻¹, 728±2 cm⁻¹, 717±2 cm⁻¹, 700±2 cm⁻¹, 674±2 cm⁻¹, 655±2cm⁻¹, 630±2 cm⁻¹, 586±2 cm⁻¹, 569±2 cm⁻¹, 539±2 cm⁻¹, 502±2 cm⁻¹, 444±2cm⁻¹, 421±2 cm⁻¹, 401±2 cm⁻¹, 388±2 cm⁻¹, 363±2 cm⁻¹, 353±2 cm⁻¹, 301±2cm⁻¹, 279±2 cm⁻¹, 234±2 cm⁻¹, 208±2 cm⁻¹, 170±2 cm⁻¹, 116±2 cm⁻¹;

where the signals which are underlined are those which differ from thesignals in the other polymorphic forms of Compound 1 by at least 2 cm⁻¹.

This polymorphic form (known as Form 3) is thermodynamically stable attemperatures above about 60-65° C. Furthermore, Form 3 is the mostsoluble crystalline form of Compound 1 in both fasted state and fedstate simulated intestinal fluid and this may prove advantageous bothfor formulation purposes and for its bioavailability in vivo.

It has also been found that Polymorphic Form 3 of Compound 1, optionallyin admixture with Polymorphic Form 2, is a useful starting material forthe preparation of pure Polymorphic Form 2.

Polymorphic Form 3 has a melting signal at 200° C. as measured bydifferential scanning calorimetry and is stable at temperatures aboveabout 60-65° C. Below this temperature, Form 2 is the thermodynamicallymore stable form, with Form 1 being the thermodynamically stable form atvery high temperatures, although it is difficult to determine atransition temperature between Forms 2 and 3 as the measurement isusually carried out using a suspension equilibration experiment with amixture of the different forms of Compound 1 and, in this experiment,Compound 1 appears to decompose before the transition temperature isreached.

Suitably, Polymorphic Form 3 of Compound 1 will be pure or substantiallypure. Thus, it will usually comprise not more than 10% of other forms ofCompound 1, preferably not more than 5%, more preferably not more than2% and most preferably not more than 1% of other forms of Compound 1.The other forms of Compound 1 may be the amorphous form or Forms 1 or 3.

It is also preferred that the Polymorphic Form 3 of Compound 1 issubstantially free of other impurities, for example traces of solvent.Therefore, suitably, the Polymorphic Form 2 of compound 1 comprises notmore than 1% by weight of solvent (e.g. methylethylketone). Moresuitably it comprises not more than 0.5% by weight preferably not morethan 0.2% and more preferably not more than 0.1% by weight.

A method for the preparation of Compound 1 is set out in WO2009/090414.However, as already discussed, the method described appears to lead toan amorphous form of the compound. Recrystallisation of this productgave rise to polymorphic Form 1.

Polymorphic Form 3 may be prepared from the product described inWO2009/090414 by phase equilibration for a prolonged period, typically15 to 30 days at room temperature in methylethylketone. In some cases,Polymorphic form 2 is obtained in admixture with polymorphic form, Form3.

Therefore, where necessary, Polymorphic Form 3 may be obtained from amixture of Forms 2 and 3 by further phase equilibration inmethylethylketone at elevated temperature, typically 60 to 80° C., butmore usually at 65 to 80° C. and typically 70-75° C., for a period ofabout 20-36 hours, but suitably 24-26 hours.

If a still purer product is required, the process may comprise seeding asaturated solution of Compound 1 in methylethyletone at an elevatedtemperature of about 65 to 80° C., more usually 70-75° C., with crystalsof Polymorphic Form 3 obtained from the step above and allowingcrystallisation to take place, followed by isolating the crystals ofpolymorphic Form 3.

Therefore, in a further aspect of the invention there is provided aprocess for the preparation of Polymorphic form 2 of[5-fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-aceticacid as defined above, the process comprising:

a. suspending [5-fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-acetic acid inmethylethylketone;

b. stirring the suspension at a temperature of about 15 to 25° C. for 15to 30 days; and

c. isolating and drying the crystalline[5-fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-acetic acid.

After this process is carried out, the product will generally be amixture of Polymorphic Forms 2 and 3.

Therefore, the process may further comprise the steps of:

d. dissolving the product of step (c) in methyl ethyl ketone at anelevated temperature of from about 65 to 80° C. to obtain a saturatedsolution;

e. partially evaporating the solvent;

f. stirring the mixture for 20-36 hours such that crystallisation takesplace; and

g. isolating the crystalline Compound 1.

Optionally, the process may comprise the additional steps of:

h. preparing a saturated solution of Compound 1 in methylethylketone atan elevated temperature of about 65-80° C.;

i. seeding the solution with the crystalline product of step (g);

j. allowing crystallisation to take place and;

k. isolating the crystalline product.

Optionally, steps (h) to (k) may be repeated using the product of step(k) as the seed crystals for the next crystallisation step.

The starting Compound 1 used in the process may be amorphous material,polymorphic Form 1 or polymorphic Form 2 mixtures of any of these.However, this process is particularly useful when starting fromamorphous material, for example material obtained from the processdescribed in WO2009/090414.

The phase equilibration is more typically carried out over about 15 to20 days, for example 17 days.

Polymorphic Form 3 is, of course, useful as a pharmaceutical but, inaddition, it has been found to be the most suitable starting material inthe preparation of Polymorphic Form 2, which is the mostthermodynamically stable form at temperatures up to about 65° C.

As described in our co-pending application, Polymorphic Form 2 ofCompound 1 can be prepared by preparing a saturated solution ofPolymorphic Form 3 of Compound 1 in acetonitrile or in a mixture ofacetonitrile and water, seeding the solution with crystals ofPolymorphic Form 2 and allowing crystallisation to take place.

As discussed in WO2009/090414, Compound 1 has CRTH2 antagonist activityand is therefore useful in the treatment of conditions which aremediated by PGD₂ or other agonists binding to CRTH2.

Thus, in a further aspect of the invention there is provided PolymorphicForm 3 of [5-fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-acetic acid as defined abovefor use in medicine, particularly in the treatment or prevention ofallergic diseases, asthmatic conditions and inflammatory diseases,examples of which are asthma, asthma exacerbations, chronic obstructivepulmonary disease, allergic rhinitis conjunctivitis, nasal polyps,atopic dermatitis, contact hypersensitivity (including contactdermatitis), eosinophilic cough, eosinophilic bronchitis, eosinophilicgastroenteritis, eosinophilic oesophagitis, food allergies, inflammatorybowel disease, ulcerative colitis, Crohn's disease, mastocytosis,urticaria, hypereosinophilic syndrome, hyper IgE syndrome, fibroticdiseases, Churg-Strauss syndrome and multiple sclerosis.

The compound is also of use in the treatment of infection.

The term “asthma” includes all types of asthma, for example allergicasthma, non allergic asthma, eosinophilic asthma, steroid resistantasthma, Th2 dependent asthma, non-Th2 dependent asthma and aspirininduced asthma. In one embodiment, the asthma is allergic asthma and inanother embodiment the asthma is eosinophilic asthma.

“Asthma exacerbations” includes exacerbations induced by viralinfections, especially infection with respiratory syncytial virus (RSV)or rhinovirus.

Allergic rhinitis includes both perennial allergic rhinitis and seasonalallergic rhinitis.

“Conjunctivitis” includes, in particular, allergic conjunctivitis,vernal keratoconjunctivitis and atopic keratoconjunctivitis.

“Infection” includes bacterial, viral or fungal infection. The infectionmay occur in patients who are atopic or are at risk of becoming atopicand may be, for example a rhinovirus, influenza or RSV infection,especially in asthmatic patients. Alternatively, the infection may be abacterial infection for example a Staphylococcus aureus infection,particularly in patients suffering from atopic dermatitis.

The term “fibrotic diseases” includes, in particular, fibrotic diseasescaused/exacerbated by Th2 immune responses, for example idiopathicpulmonary fibrosis, scleroderma and hypertrophic scars.

Polymorph 3 of Compound 1 may also be of use in the treatment of otherPGD2-mediated diseases. Diseases which may be mediated by PGD2 includeautoimmune diseases such as systemic lupus erythematus, psoriasis, acne,allograft rejection, rheumatoid arthritis, psoriatic arthritis andosteoarthritis.

The invention further provides a method for the treatment or preventionof a disease or condition selected from those listed above, the methodcomprising administering to a patient in need of such treatment aneffective amount of Polymorphic Form 3 of Compound 1 as defined above.

The patient will be a mammal, for example a human.

There is also provided the use of Polymorphic Form 3 of Compound 1 asdefined above in the preparation of an agent for the treatment orprevention of a disease or condition selected from those listed above.

Polymorphic Form 3 of [5-fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-acetic acid must be formulatedin an appropriate manner depending upon the diseases or conditions it isrequired to treat.

Therefore, in a further aspect of the invention there is provided apharmaceutical or veterinary composition comprising Polymorphic Form 3of [5-fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-acetic acid as defined abovetogether with a pharmaceutically or veterinarily acceptable excipient.Other active materials may also be present, as may be consideredappropriate or advisable for the disease or condition being treated orprevented.

The excipient, or, if more than one be present, each of the excipients,must be acceptable in the sense of being compatible with the otheringredients of the formulation and not deleterious to the recipient.

The formulations include those suitable for oral (including viscous oralformulations), rectal, nasal, bronchial (inhaled), topical (includingeye drops, buccal and sublingual), vaginal or parenteral (includingsubcutaneous, intramuscular, intravenous and intradermal) administrationand may be prepared by any methods well known in the art of pharmacy.

The route of administration will depend upon the condition to be treatedbut preferred compositions are formulated for oral, nasal, bronchial ortopical administration.

The composition may be prepared by bringing into association PolymorphicForm 3 of [5-fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-acetic acid with the excipient.In general, the formulations are prepared by uniformly and intimatelybringing into association the active agent with liquid carriers orfinely divided solid carriers or both, and then if necessary shaping theproduct. The invention extends to methods for preparing a pharmaceuticalcomposition comprising bringing Polymorphic Form 3 of[5-fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-acetic acid in conjunction orassociation with a pharmaceutically or veterinarily acceptableexcipient.

Formulations for oral administration in the present invention may bepresented as: discrete units such as capsules, sachets, tablets, trochesor lozenges each containing a predetermined amount of Polymorph 2 ofCompound 1; as a powder or granules; as a solution or a suspension ofthe active agent in an aqueous liquid or a non-aqueous liquid; or as anoil-in-water liquid emulsion or a water in oil liquid emulsion; or as asyrup or elixir; or as a bolus, etc.

For compositions for oral administration (e.g. tablets, capsules,formulations comprising a mucoadherent etc), the term “acceptablecarrier” includes vehicles such as common excipients e.g. bindingagents, for example syrup, acacia, gelatin, sorbitol, tragacanth,polyvinylpyrrolidone (povidone), methylcellulose, ethylcellulose, sodiumcarboxymethylcellulose, hydroxypropylmethylcellulose, sucrose andstarch; fillers and carriers, for example corn starch, gelatin, lactose,sucrose, microcrystalline cellulose, kaolin, mannitol, dicalciumphosphate, sodium chloride and alginic acid; wetting agents/surfactantssuch as poloxamers, polysorbates, sodium docusate and sodium laurylsulfate; disintegrants such as starch or sodium starch glycolate; andlubricants such as magnesium stearate, sodium stearate and othermetallic stearates, glycerol stearate, stearic acid, silicone fluid,talc waxes, oils and colloidal silica. Sweetening agents and flavouringagents such as peppermint, oil of wintergreen, cherry flavouring and thelike can also be used. It may be desirable to add a colouring agent tomake the dosage form readily identifiable. Tablets may also be coated bymethods well known in the art.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine Polymorphic Form 3 of Compound 1 in afree flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, preservative, surface-active ordispersing agent. Moulded tablets may be made by moulding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide slow or controlled release of the activeagent.

Some formulations may comprise a mucoadherent, for example amucopolysaccharide such as sodium hyaluronate. Such compositions may beformulated as, for example, liquids, liquid syrups, soft gels, liquidgels, flowable gels or aqueous suspensions and may, in addition to theactive agent and the mucoadherent, also contain one or more additionalexcipients as set out above. Liquid formulations will usually alsocontain a liquid carrier, which may be a solvent or suspending agent,for example water or saline solution and may also contain a substance toincrease their viscosity, for example sodium carboxymethylcellulose,sorbitol or dextran.

Other formulations suitable for oral administration include lozengescomprising the active agent in a flavoured base, usually sucrose andacacia or tragacanth; pastilles comprising Polymorphic Form 3 ofCompound 1 in an inert base such as gelatin and glycerin, or sucrose andacacia; and mouthwashes comprising the active agent in a suitable liquidcarrier.

For topical application to the skin, the composition may be made up intoa cream, ointment, jelly, solution or suspension etc. Cream or ointmentformulations that may be used for Polymorphic Form 3 of Compound 1 areconventional formulations well known in the art, for example, asdescribed in standard text books of pharmaceutics such as the BritishPharmacopoeia.

The composition defined above may be used for the treatment of therespiratory tract by nasal, bronchial or buccal administration of, forexample, aerosols or sprays which can disperse the pharmacologicalactive ingredient in the form of a powder or in the form of drops of asolution or suspension. Pharmaceutical compositions withpowder-dispersing properties include dry powder inhalers and metereddose inhalers. Dry powder inhalers usually contain, in addition toPolymorphic Form 3 of Compound 1, a suitable carrier such lactose and,if desired, adjuncts, such as surfactants and/or diluents and/or flowaids and/or lubricants. Metered dose inhalers for dispersing powdersusually contain, in addition to the Polymorphic Form 3 of Compound 1, aliquid propellant with a boiling point below room temperature and, ifdesired, adjuncts, such as liquid or solid non-ionic or anionicsurfactants and/or diluents. Pharmaceutical compositions for treatmentof the respiratory tract in which the pharmacologically activeingredient is in solution (e.g., either solution for nebulisation ormetered dose inhalers) contain, in addition to this, a suitablepropellant, and furthermore, if necessary, an additional solvent and/ora stabiliser. Instead of the propellant, compressed air can also beused, it being possible for this to be produced as required by means ofa suitable compression and expansion device.

Parenteral formulations will generally be sterile.

Typically, the dose of Compound 1 will be about 0.01 to 100 mg/kg; so asto maintain the concentration of drug in the plasma at a concentrationeffective to inhibit PGD₂ at the CRTH2 receptor. The precise amount ofCompound 1 which is therapeutically effective, and the route by whichsuch compound is best administered, is readily determined by one ofordinary skill in the art by comparing the blood level of the agent tothe concentration required to have a therapeutic effect.

The pharmaceutical composition is most suitably formulated as aonce-a-day administration, although more frequent dosing may be used insome cases, for example twice, three times or four times daily dosing.On the other hand, it may sometimes be possible to dose less frequentlythan once daily, for example once every two days. In some circumstancesa dosage regimen may be used in which the composition is administeredfor a first period and then, during a second period, administrationceases or, alternatively, the composition administered at a lower dose.Such a dosage regimen is described in WO 2009/063202.

Polymorphic Form 3 of Compound 1 as defined above may be used incombination with one or more active agents which are useful in thetreatment of the diseases and conditions listed above, although theseactive agents are not necessarily inhibitors of PGD₂ at the CRTH2receptor.

Therefore, the pharmaceutical composition described above mayadditionally contain one or more of these active agents.

There is also provided the use of Polymorphic Form 3 of Compound 1 asdefined above in the preparation of an agent for the treatment ofdiseases and conditions mediated by CRTH2 receptor agonists, especiallyPGD₂, wherein the agent also comprises an additional active agent usefulfor the treatment of the same diseases and conditions.

These additional active agents may be other CRTH2 receptor antagonistsor may have a completely different mode of action. They include existingtherapies for allergic and other inflammatory diseases including:

Suplatast tosylate and similar compounds;

β2 adrenoreceptor agonists such as metaproterenol, isoproterenol,isoprenaline, albuterol, salbutamol, formoterol, salmeterol,indacaterol, terbutaline, orciprenaline, bitolterol mesylate andpirbuterol or methylxanthines such as theophylline and aminophylline,mast cell stabilisers such as sodium cromoglycate or muscarinic receptorantagonists such as tiotropium;

antihistamines, for example histamine H₁ receptor antagonists such asloratadine, cetirizine, desloratadine, levocetirizine, fexofenadine,astemizole, azelastine and chlorpheniramine or H₄ receptor antagonists;

α₁ and α₂ adrenoreceptor agonists such as propylhexedrine phenylephrine,phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride,oxymetazoline hydrochloride, tetrahydrozoline hydrochloride,xylometazoline hydrochloride and ethylnorepinephrine hydrochloride;

modulators of chemokine receptor function, for example CCR1, CCR2,CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11(for the C—C family) or CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for theC—X—C family) and CX₃CR1 for the C—X₃—C family;

Leukotriene antagonists such as montelukast, pranlukast and zafirlukast

leukotriene biosynthesis inhibitors such as 5-lipoxygenase inhibitors or5-lipoxygenase activating protein (FLAP) inhibitors such as zileuton,ABT-761, fenleuton, tepoxalin, Abbott-79175,N-(5-substituted)-thiophene-2-alkylsolfonamides, 2,6-di-tert-butylphenolhydrazones, methoxytetrahydropyrans such as ZD2138, SB-210661,pyridinyl-sub stituted-2-cyanonaphthalene compounds such as L-739010,2-cyanoquinoline compounds such as L-746,530, indole and quinolinecompounds such as MK-591, MK-886 and BAY x 1005;

Phosphdiesterase inhibitors, including PDE4 inhibitors such asroflumilast;

anti-IgE antibody therapies such as omalizumab;

anti-infectives such as fusidic acid (particularly for the treatment ofatopic dermatitis);

anti-fungals such as clotrimazole (particularly for the treatment ofatopic dermatitis);

immunosuppressants such as tacrolimus and particularly pimecrolimus inthe case of inflammatory skin disease or alternatively FK-506,rapamycin, cyclosporine, azathioprine or methotrexate;

Immunotherapy agents including allergen immunotherapy such as Grazax;

corticosteroids such as prednisone, prednisolone, flunisolide,triamcinolone acetonide, beclomethasone dipropionate, budesonide,fluticasone propionate mometasone furoate and fluticasone furoate drugswhich promote Th1 cytokine response such as interferons, TNF or GM-CSF.

CRTH2 antagonists may also be combined with therapies that are indevelopment for inflammatory indications including:

other antagonists of PGD₂ acting at other receptors such as DPantagonists;

drugs that modulate cytokine production such as inhibitors of TNFαconverting enzyme (TACE) anti-TNF monoclonal antibodies, TNF receptorimmunoglobulin molecules, inhibitors of other TNF isoforms,non-selective COX-1/COX-2 inhibitors such as piroxicam, diclofenac,propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofenand ibuprofen, fenamates such as mefanamic acid, indomethacin, sulindacand apazone, pyrazolones such as phenylbutazone, salicylates such asaspirin; COX-2 inhibitors such as meloxicam, celecoxib, rofecoxib,valdecoxib and etoricoxib, low dose methotrexate, lefunomide,ciclesonide, hydroxychloroquine, d-penicillamine, auranofin orparenteral or oral gold;

drugs that modulate the activity of Th2 cytokines IL-4 and IL-5 such asblocking monoclonal antibodies and soluble receptors;

PPAR-γ agonists such as rosiglitazone; or with

anti-RSV antibodies such as Synagis (palivizumab) and agents that may beused to treat rhinovirus infection in the future e.g. intereferon-alpha,interferon-beta or other interferons.

Combinations of Polymorphic Form 3 of Compound 1 as defined above withleukotriene antagonists such as montelukast, pranlukast and zafirlukastare particularly suitable, especially combinations with montelukast.

In yet a further aspect of the invention, there is provided a productcomprising Polymorphic Form 3 of Compound 1 as defined above and one ormore of the agents listed above as a combined preparation forsimultaneous, separate or sequential use in the treatment of a diseaseor condition mediated by the action of PGD₂ at the CRTH2 receptor.

In yet another aspect of the invention there is provided a kit for thetreatment of a disease or condition mediated by the action of PGD₂ atthe CRTH2 receptor comprising a first container comprising PolymorphicForm 3 of Compound 1 as defined above and a second container comprisingone or more of the active agents listed above.

The invention will now be described in greater detail with reference tothe examples and to the following drawings in which:

FIG. 1 shows the PXRD pattern of Compound 1, Batch 1.

FIG. 2 shows the PXRD pattern of Compound 1, Batch 3.

FIG. 3 shows the FT-Raman spectrum of Compound 1, Batch 3. The spectrumwas used as a reference for the preliminary polymorphism study. The mostpronounced Raman peaks are labeled in the figure.

FIG. 4 shows a plot of TG-FTIR of Compound 1, Batch 3 in a temperaturerange of 25° C. to 250° C. and a heating rate of 10° C./min.

FIG. 5 is a differential scanning calorimetry trace for Compound 1,Batch 1.

FIG. 6 is a dynamic vapour sorption curve for Compound 1, Batch 1showing relative humidity over the sample and sample weight percentversus time.

FIG. 7 is a further dynamic vapour sorption curve for Compound 1, Batch1 showing sample weight percent against relative humidity.

FIG. 8 shows the PXRD pattern of Compound 1, Batch 2.

FIG. 9 shows the PXRD pattern of the product obtained by recrystallisingCompound 1, Batch 1 from ethyl acetate and then drying the crystallinesolid obtained (Example 3).

FIG. 10 is a detail of the PXRD pattern of the recrystallised and driedproduct from Example 3 (Polymorphic Form 1) showing the fit between theexperimental pattern of the product of Example 3 (Form 1; red, file:H906) and the data calculated based upon a LeBail-fit (blue). Below isthe difference plot shown in red.

FIG. 11 is a ¹H NMR plot of the product of Experiment P15 of Example 4(Polymorphic Form 1) in DMSO-d6.

FIG. 12 shows FT-Raman spectrum of the product of Experiment P9 ofExample 4 (Polymorphic Form 2).

FIG. 13 shows the PXRD pattern of the product of Experiment P9 ofExample 4 (Polymorphic Form 2). The material is crystalline.

FIG. 14 is a ¹H NMR was recorded of the product of Experiment P9 ofExample 4 (Form 2) in DMSO-d6.

FIG. 15 shows the FT-Raman spectrum of Product P6 of Example 4 (Form 3in a mixture with Form 2).

FIG. 16 is a detail of the PXRD pattern of Product P6 of Example 4 incomparison with that of Product P9 of Example 4 (Form 2)

FIG. 17 is a detail of the PXRD pattern of Product P24 of Example 6(Polymorphic Form 2) showing the fit between the experimental pattern ofProduct P24 (red, file: J893) and the data calculated based upon aLeBail-fit (blue). Below is the difference plot shown in red.

FIG. 18 shows the PRXD pattern of Polymorphic Form 3 (the product ofExample 6).

FIG. 19 shows the FT Raman spectrum of Polymorphic Form 3 (the productof Example 6).

In the Examples the following conditions were used for measurements.

1H-NMR: 1H-NMR spectra were recorded using a Bruker DPX300 spectrometerwith a proton frequency of 300.13 MHz, a 30° excitation pulse, and arecycle delay of 1 s. 16 scans were accumulated. d6-DMSO was used as thesolvent.

DSC: Differential scanning calorimetry was carried out with a PerkinElmer DSC-7 instrument (closed gold sample pan under N₂ atmosphere).

DVS (SPS): Sorption Measurement System SPS11-100n. The sample was placedin an Al crucible, and the sample was allowed to equilibrate at a givenr.h. before starting a predefined humidity program. The used measurementprogram can be recognized in the corresponding figures (blue line).

FT-Raman spectroscopy: FT-Raman spectra were recorded on a Bruker RFS100 FTRaman system with a near infrared Nd:YAG laser operating at 1064nm and a liquid nitrogen-cooled germanium detector. For each sample, aminimum of 64 scans with a resolution of 2 cm⁻¹ were accumulated. 300 mWlaser power was used. The FTRaman data are shown in the region between3500 to 100 cm⁻¹. Below 100 cm-1 the data are meaningless due to thefilter cut-off.

Powder X-ray diffraction: Bruker D8; Copper Ka radiation, 40 kV/40 mA;LynxEye detector, 0.02° 2 Theta step size, 37 s step time. Samplepreparation: The samples were generally measured without any specialtreatment other than the application of slight pressure to get a flatsurface. Silicon single crystal sample holders were used (0.1 mm deep).The samples were rotated during the measurement.

Solvents: For all experiments, Fluka, Merck or ABCR analytical gradesolvents were used.

TG-FTIR: Thermogravimetric measurements were carried out with a NetzschThermo-Microbalance TG 209 coupled to a Bruker FTIR Spectrometer Vector22 or IFS 28 (sample pans with a pinhole, N2 atmosphere, heating rate10° C./min, range 25° C. up to 250° C.).

In the examples, the following abbreviations are used:

DMSO Dimethylsulfoxide

EtOAc Ethyl acetate

DCM Dichloromethane

TMSOTf Trimethylsilyl triflate

HPLC High performance liquid chromatography

MP Melting Point

LCMS Liquid chromatography mass spectrometry

TLC Thin layer chromatography

THF Tetrahydrofuran

MTBE Methyl ^(t)butyl ether

DMF N,N′-dimethylformamide

NMP N-Methyl-2-pyrrolidone

MEK Methylethylketone

Example 1—Preparation of[5-fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-aceticacid (Compound 1)

Compound 1 was prepared by the method set out in WO2009/090414 which isas follows.

i. 2-(4-Fluorobenzenesulfonyl)-pyridine-3-carboxaldehyde

2-Chloro-3-pyridinecarboxaldehyde (4.04 g, 2.86 mmol) and4-fluorobenzenesulfinic acid sodium salt (5.73 g, 3.14 mmol) weredissolved in DMSO (100 ml) and the mixture was heated at 100° C. for 72h under nitrogen. Upon cooling to ambient the mixture was diluted withwater (500 ml) and extracted with EtOAc (3×). The combined organics werewashed with water, brine, dried (MgSO₄) and evaporated to dryness toafford 7.89 g of crude product. The crude compound was pre-absorbed ontosilica and purified by dry pad suction column chromatography, elutingwith heptane using an EtOAc gradient, to afford 4.14 g (41%) of thedesired product as a yellow solid (plates) (MP=131-131.3° C.; IR=1691cm⁻¹; HPLC=7.21 min>99%).

¹H NMR (400 MHz; CDCl₃): 7.23-7.29 (2H, m) 7.60 (1H, dd) 8.05-8.10 (2H,m) 8.37 (2H, dd) 8.67 (1H, dd) 11.1 (1H, s).

¹³C NMR (100 MHz, CDCl₃): 116.6 (d) 116.8 (d) 127.3 (d) 130.7 (s) 132.6(d) 134.0 (s) 137.9 (d) 152.5 (s) 159.7 (s) 165.1 (s) 167.7 (s) 188.5(d).

ii.[5-Fluoro-3-({2-[4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-aceticacid ethyl ester

A solution of (5-fluoro-2-methyl-indol-1-yl)-acetic acid ethyl ester(1.0 g, 4.4 mmol) and2-(4-fluorobenzenesulfonyl)-pyridine-3-carboxaldehyde (1.13 g, 4.3 mmol)in dry DCM (50 ml) was added over 5-10 min to a stirred solution ofTMSOTf in dry DCM (15 ml) at 0° C. The mixture was aged for 15 minbefore the addition of neat triethylsilane (2.05 ml, 12.8 mmol) in oneportion. The mixture was stirred for a further 15 h and allowed to warmup to ambient. The reaction was quenched by the drop wise addition ofsaturated NaHCO₃ solution (10 ml) and the biphasic mixture extractedwith DCM (2×50 ml). The combined organics were washed with brine (50 ml)then dried (MgSO₄) and evaporated to dryness. The reaction was repeatedon an identical scale and the two crude materials were purifiedseparately. The crude reaction materials were purified by columnchromatography using heptane and an ethyl acetate gradient to afford0.90 g (43%) and 1.50 g (72%) of the desired compound as a pale purplesolid and a brown solid respectively of differing purities (96.0% and94.5% by HPLC) (MP=150.5-151.5° C., IR=1751 cm⁻¹; HPLC=12.24 min).

¹H NMR (400 MHz; CDCl₃): 1.26 (3H, t) 2.29 (3H, s) 4.22 (2H, q) 4.62(2H, s) 4.80 (2H, s) 6.79 (1H, dd) 6.86 (1H, ddd) 7.10 (1H, dd) 7.19(1H, dd) 7.23-7.28 (2H, m) 7.36 (1H, dd) 8.05-8.11 (2H, m) 8.29 (1H,dd).

¹³C NMR (100 MHz, CDCl₃): 10.4 (q) 14.2 (q) 25.3 (t) 45.2 (t) 61.9 (t)103.4 (d) 103.6 (d) 108.0 (s) 108.1 (s) 109.1 (d) 109.2 (d) 109.5 (d)109.8 (d) 116.2 (d) 116.4 (d) 127.0 (d) 128.5 (s) 128.6 (s) 132.2 (d)132.3 (d) 133.3 (s) 135.1 (s) 136.4 (s) 136.6 (s) 139.4 (d) 146.2 (d)156.2 (s) 157.0 (s) 159.4 (s) 164.7 (s) 167.3 (s) 168.6 (s).

iii.[5-Fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-aceticacid (Compound 1)

Method A

KOH (0.34 g, 5.94 mmol) was dissolved in water (7 ml) and added to avigorously stirred solution of[5-fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridine-3-yl}methyl)-2-methylindol-1-yl]-aceticacid ethyl ester (0.96 g, 1.98 mmol) in THF (21 ml) under nitrogen atambient. The reaction was monitored by TLC and LCMS. After 2 h thesolvent was removed in vacuo before adjusting the pH to 1.5 using 0.1MHCl solution. The precipitate was stirred vigorously for 15 min beforebeing isolated by suction filtration. The collected solid was washedwith water and then MTBE, pulled dry in air and then dried in vacuo at50° C. to afford 870 mg (97%) of the product as a pink solid(MP=125-126° C.; IR=1729 cm⁻¹; HPLC=10.80 min 99.3%).

¹H NMR (400 MHz; DMSO): 2.29 (3H, s) 4.56 (2H, s) 4.97 (2H, s) 6.85-6.91(2H, m) 7.37-7.7.45 (2H, m) 7.47 (1H, dd) 7.51-7.57 (2H, m) 8.06-8.15(2H, m) 8.36 (1H, dd).

¹³C NMR (100 MHz, DMSO): 10.5 (q) 25.0 (t) 45.5 (t) 102.7 (d) 102.9 (d)107.7 (s) 107.8 (s) 108.8 (d) 109.1 (d) 110.9 (d) 111.0 (d) 117.1 (d)117.3 (d) 128.1 (d) 128.2 (d) 128.3 (d) 132.7 (d) 132.8 (d) 133.8 (d)135.5 (s) 136.8 (s) 138.1 (s) 140.4 (d) 147.0 (d) 155.9 (s) 156.6 (s)158.9 (s) 164.6 (s) 167.1 (s) 171.1 (s).

Batches 1 and 3 of Compound 1 used below were prepared by the methoddescribed above, which is identical to the method set out inWO2009/090414. For Batch 2 of Compound 1, the following procedure wasused.

Method B

KOH (0.514 g, 9.16 mmol) was dissolved in water (11 ml) and added to avigorously stirred solution of[5-fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-aceticacid ethyl ester (1.48 g, 3.05 mmol) in THF (32 ml) under nitrogen atambient. The reaction was monitored by TLC and LCMS. After 2 h, thereaction vessel contained a basic aqueous solution of the potassium saltof compound 1. Instead of removing the solvent as set out inWO2009/090414, the aqueous solution was washed with ethyl acetate toobtain a suspension. The precipitated solid was removed by filtrationand the pH of the aqueous phase adjusted to 1.5 using 0.1M HCl solutionand stirring vigorously for 15 minutes, before being isolated by suctionfiltration. The collected solid was washed with water and then MTBE,pulled dry in air and then dried in vacuo at 50° C. to afford 900 mg(64%) of the product as a tan solid.

Example 2—Characterisation of the Product of Example 1

Three batches of product prepared by the method of Example 1 werecharacterised by FT-Raman spectroscopy, X-ray powder diffraction (PXRD),Thermogravimetry coupled to Fourier Transform Infrared Spectroscopy(TG-FTIR), differential scanning calorimetry (DSC) and DVS

FIG. 1 shows the PXRD pattern of Batch 1. The sample was measured asreceived. The material is amorphous. The signals at 28.4 °2 Theta and40.5 °2 Theta could most likely be assigned to KCl.

FIG. 2 shows the PXRD pattern of Batch 3, measured as received. Thesample is amorphous. The signal at 28.3 °2 Theta could most likely beassigned to KCl.

FIG. 3 shows the FT-Raman spectrum of Batch 3. The spectrum was used asa reference for the preliminary polymorphism study. The most pronouncedRaman peaks are labeled in the figure.

Batch 3 was analyzed by TG-FTIR in a temperature range of 25° C. to 250°C. and a heating rate of 10° C./min. TG-FTIR shows a loss of 1.2 wt.-%mass (residual H₂O) from r.t. to 160° C. Decomposition occurs above˜160° C. Therefore the material is likely a non-solvated form. This isshown in FIG. 4.

Batch 1 was also analyzed by differential scanning calorimetry and FIG.5 shows the DSC trace. In the first scan (red trace) a glass transitionpoint at about 79° C. (ΔCp: 0.4 J/g*° C.) and a recrystallization signalat about 155° C. is observed. After cooling the sample is stillpartially amorphous. In the second heating step (blue trace) a glasstransition point at about 73° C. with a ΔCp of 0.2 J/g*° C. and amelting signal at about 200° C. with subsequent degradation is observed.The shift of the glass transition point to lower temperatures isprobably due to partial decomposition during the first heating step.

In order to examine the behaviour of Batch 1 in the presence of variablewater vapour pressure, the sample was analyzed by DVS. The resulting DVScurve with relative humidity over the sample and sample weight percentversus time is shown in FIG. 6. FIG. 7 shows sample weight percentagainst relative humidity plot. The sample was conditioned at 50% r.h.before starting a pre-defined humidity program with a scanning rate of5% r.h. change per hour. Below 50% r.h. a continuous mass loss isobserved. The sample shows in the second step (0% r.h up to 95% r.h.) acontinuous water uptake. At relative humidities above 84% r.h. anincreased water uptake is observed. At 95% r.h. no equilibrium isreached. This is typical for amorphous material. At the end of themeasurement (end humidity 50% r.h.) the sample has a 0.6% higher mass asthe starting material. The sample was checked by FT-Raman (pre- and postDVS measurements). The sample recovered from DVS shows no phasetransition.

Similar results were obtained for Batch 3.

Unlike Batches 1 and 3, the PXRD pattern of Batch 2 (FIG. 8) showed thatthe material was crystalline. The material was prepared using thealternative procedure, Method B, set out above.

Example 3—Recrystallization of Batch 1 of Compound 1

Prior to the salt screening, the KC1 impurity was removed bycrystallization of 5 g of Batch 1 of Compound 1 in ethyl acetate. Theproduct was characterized by FT-Raman and TG-FTIR. The TG-FTIRmeasurement showed a mass loss of 8.2% ethyl acetate at 140° C., whichis above the boiling point. This shows that the solvent is stronglybound and is typical for a solvate formation. The sample was dried undervacuum at r.t. and the product was characterized by FT-Raman, TG-FTIRand PXRD. The material changed after drying to a non-solvated formbecause ethyl acetate was not longer detectable by TG-FTIR. FIG. 9 showsthe PXRD pattern of the recrystallised product. The material iscrystalline.

The PXRD pattern showed that this recrystallised and dried product wasthe same crystalline form as Batch 2 of Compound 1 and this crystallineform was designated Form 1.

Example 4—Suspension Equilibration and Cooling CrystallisationExperiments

About 100 mg of Batch 3 was suspended in solvents and solvents mixturesand stirred for 17 days at 22° C. The solids were filtered and analyzedby FT-Raman spectroscopy (2 measurements: 1. wet material, 2. driedmaterial).

An additional suspension equilibration experiment (Exp P23) according tothe manufacturing process was performed. To 250 mg of Batch 3, 62.5 μLwater and 440 μL formic acid (98%) were added. A yellowish brownsuspension was observed. 95 μL toluene was added. After short sonicationprecipitation was observed. Stirring was not possible. Additionally 1 mLH₂O and 80 μL toluene were added. The temperature has being cycledbetween 25° C. for one hour and 50° C. for two hours (using two hourramp times) for a total of three days.

For the cooling crystallization experiments, about 100 mg Batch 3 wasdissolved at higher temperatures in appropriate amounts of solvent toobtain a saturated solution. To prepare a seed free solution, thetemperature was further increased by 5° C. The solutions weresubsequently cooled to 5° C. The solids were filtered and analyzed byFT-Raman spectroscopy (2 measurements: 1. wet material, 2. driedmaterial). If no solid was obtained, the solutions were stirred orstored at 5° C. and if still no precipitation was observed, thesolutions were evaporated under nitrogen at r.t.

New forms were further characterized by PXRD and TG-FTIR.

Table 1 summarizes the results of the suspension equilibration andcooling crystallization experiments.

TABLE 1 Results of the suspension equilibration and coolingcrystallization experiments. Exp # Type 1) Solvent T [° C.] Raman 2)PXRD 2) Comments P2 SL Benzyl alcohol 22 New New probably benzyl alcoholsolvate; P3 SL DMF/TMBE 22 New New probably DMF 1:5 solvate; TG-FTIRshows a loss of DMF along with the decomposition. P4 SL DMSO 22 New NewDMSO solvate; TG-FTIR shows a loss of DMSO along with the decompositionP5 SL DMSO/ 22 P4 — Same as Exp. P4 toluene 1:19 P6 SL Methylethylketone22 New New non-solvated form Form 2 + Form 3 P7 SL THF 22 New ³⁾ TG-FTIRshows a loss of 12.4% of THF at ≥100° C.; (theoretical content for monosolvate: 13.6%); after drying the FT Raman agrees with that of Batch 2and the recrystallised product of Example 3, i.e. Form 1 P8 SL NMP/ 22New New Solvate cyclohexane 1:1 P9 SL water/acetonitrile 22 New NewNon-solvated 1:1 (aw: ~0.92) form: Form 2 P10 SL water/THF 1:1 22 NewNew TG-FTIR shows (aw: ~1) a loss of 42.5% of water; most likelyhydrate + surface bound water P11 SL methanol 22 New New TG-FTIR shows aloss of 6.4% of MeOH ≥110° C.; (theoretical content for mono solvate:6.6%) P12 SL Acetonitrile 22 P9 — Agrees with Exp P9, i.e. Form 2 P13 SLAcetone 22 New ³⁾ TG-FTIR shows a loss of 7.7% of acetone ≥110° C.;(theoretical content for hemi solvate: 6.0%); after drying the FT Ramanagrees with that of Batch 2 and the recrystallised product of Example 3,i.e. Form 1 P14 SL Formic acid 22 New ³⁾ TG-FTIR shows a loss of 8.2% offormic acid; most likely solvate + surface bound solvent; after dryingthe FT Raman agrees with that of Batch 2 and the recrystallised productof Example 3, i.e. Form 1 P15 SL Dichloromethane 22 Form 1 — FT Ramanagrees with that of Batch 2 and the recrystallised product of Example 3,i.e. Form 1 P16 SL 2-propanol 22 New New TG-FTIR shows a loss of 11.9%of 2-PrOH ≥110° C.; (theoretical content for mono solvate: 11.6%) P17COL/evap water/acetone 55-5 New New TG-FTIR shows 1:1 (aw: ~0.9) a lossof 22.0% of water; most likely hydrate + surface bound water P18COL/evap TBME/Dioxane 55-5 — — gel 1:3 P20 COL Ethanol 75-5 New ³⁾TG-FTIR shows a loss of 27.7% of ethanol; most likely solvate + surfacebound solvent; after drying the FT Raman agrees with that of Batch 2 andthe recrystallised product of Example 3, i.e. Form 1 P21 COLDMSO/toluene 80-5 P4 similar to 1:9 Experiment P4, slight differences inPXRD P22 COL/evap Formic acid 80-5 New — degradation P23 SL water/formic 25-50 New New TG-FTIR shows a acid/toluene loss of 9.4% of toluene witha trace of water ≥150° C.; (theoretical content for hemi solvate:9.2%) 1) Type: SL = suspension equilibration experiment; COL: coolingcrystallization experiment. 2) new: spectrum/pattern different fromstarting material is observed which is the same as that of Form 1 (Batch2 and the recrystallised product of Example 3). ³⁾ The PXRD are similarto Compound 1, Batch 2. The recovered material from PXRD was measured byFT Raman. The spectra agree with the spectrum of Compound 1, Batch 2 andthe recrystallised product of Example 3.

In summary:

Experiments P2, P3, P4, P5, P8, P10, P11, P16, P17, P21 and P23 led tothe formation of solvates (including hydrates) or hemisolvates;

Experiment P18 gave rise to a gel product;

Experiment P22 led to a product which degraded;

Experiments P7, P13, P14, P15 and P20 gave rise to crystalline Form 1(i.e. the same polymorphic form as Batch 2 of Compound 1 and the productof Example 3);

Experiments P9 and P12 gave rise to a new crystalline form, designatedForm 2; and

Experiment P6 led to the formation of polymorphic Form 2 in admixturewith a third polymorphic form, designated Form 3.

Example 5—Further Characterisation of Polymorphic Forms

i. Polymorphic Form 1

As detailed above, the recrystallisation experiment of Example 3 gaverise to a product which was probably an ethyl acetate solvate. Ondrying, however, it changed to a non-solvated form, designated Form 1.After drying, the products of Experiments P7 (THF solvate), P13 (acetonesolvate), P14 (formic acid solvate), P15 (dichloromethane solvate) andP20 (ethanol solvate) adopted a crystalline form which appeared from theRaman spectrum to have the same characteristics as Batch 2 of Compound 1and of the recrystallised product of Example 3. Due to instability, itwas not possible to determine the stoichiometry of the solvates.

This polymorphic form was designated Form 1 and it was furthercharacterised by PXRD. Indexing of PXRD can be used to determine if agiven pattern corresponds to a pure solid phase. The PXRD pattern of therecrystallised material (file: H906) could be successfully indexed, andthe lattice was found to be triclinic. The resulting lattice parameterscan be seen in Table 2. The final fit between the observed andcalculated diffraction patterns is shown in FIG. 10 and the low R-values(see Table 2) confirm the good fit. This confirms that Form 1corresponds to a true polymorphic form and not to a mixture of forms.

TABLE 2 Lattice parameters and LeBail-Fit details for the laboratoryPXRD data for Form 1 obtained at room temperature. file H906 a 10.6 ±0.1 Å b 12.8 ± 0.1 Å c  9.1 ± 0.1 Å α 102 ± 1°   β 112 ± 1°   γ 89 ±1°   cell volume 1.116 Å³ R_(P) 3.8% weighted R_(P) 6.7%

A ¹H NMR was recorded of the product of Experiment P15 (PolymorphicForm 1) in DMSO-d6. The spectrum confirms Chemical integrity (see FIG.11).

ii. Polymorphic Form 2

Form 2 was obtained by phase equilibration experiments at roomtemperature. in water/acetonitrile (1:1) (Experiment P9) andacetonitrile (Experiment P12). The phase equilibration experiment atr.t. in ethyl methyl ketone (Experiment P6) also gave rise to Form 2 ina mixture with another new form (Form 3).

The FT-Raman Spectrum of the product of Experiment P9 of Example 4 (Form2) is shown in FIG. 12 and its PXRD pattern is shown in FIG. 13. Itcould successfully be indexed and this confirms that Form 2 correspondsto a true polymorphic form and not to a mixture of forms.

A ¹H NMR was recorded of the product of Experiment P9 of Example 4 (Form2) in DMSO-d6 (see FIG. 14). The spectrum confirms chemical integrity.

iii. Polymorphic Form 3

Form 3 was obtained as a mixture with form 2 by a phase equilibrationexperiment at r.t. in ethyl methyl ketone (Example 4, Experiment P6).FIG. 15 shows the FT-Raman spectrum of Product P6 (Form 3 in a mixturewith Form 2). The most pronounced Raman peaks are labelled in thefigure.

PXRD of Product P6 showed that the material was crystalline and FIG. 16shows the PXRD pattern of Product P6 in comparison to that of Product P9(Form 2).

Product P6 shows all signals of Product P9 and also additional signals.This indicates that Product P6 is a mixture of Form 2 and another form.This other form was designated Form 3.

Example 6—Preparation of Pure Polymorphic Form 3

A. 20.8 mg of Compound 1, mixture of Forms 2 and 3 (similar to thatobtained by the method of Example 4, P6) and 21.4 mg of Compound 1, Form2 (similar to that obtained by the method of Example 4, P9) wassuspended in 0.2 mL of MEK and the mixture heated up to 70° C. When theCompound 1 was nearly completely dissolved, a further 9.8 mg of Compound1, Form 2+Form 3 (similar to that obtained by Example 4, P6) and 10.3 mgof Compound 1, Form 1 (similar to that of Example 4, P9) was added. Thesolvent was partially evaporated under nitrogen flow, a further 0.1 mLof MEK added and the mixture stirred for 25-26 h at 75° to obtain ayellowish brown suspension. The solid was recovered by filtercentrifugation (5000 rpm, 0.2 μm PTFE, 22° C.) and the material analyzedby PXRD and shown to be Compound 1, polymorphic Form 3.

B. In order to obtain a purer Form 3 product, the crystals obtained fromA above were used to seed a saturated solution prepared as follows.286.0 mg of Compound 1, Form 1 was suspended in 0.2 mL of MEK. Themixture was sonicated for ˜1 min and precipitation was observed.Following this, an additional 0.1 mL of MEK was added, the solution washeated up to 75° C. and seeded with ˜1 mg of the crystals obtained fromA above. The solution was stirred for ˜22 h at 75° C. and a solidrecovered by filter centrifugation (0.2 μm PTFE, 1 min, 15000 rpm, 25°C.); vessel flushed with 0.05 mL of MEK. The material was dried for ˜24h under vacuum at r.t. and the solid product analyzed by FT Raman andPXRD and shown to be Compound 1, Form 3.

C. In order to obtain a still purer Form 3 product, 149.7 mg of Compound1, Polymorphic Form 1 was suspended in 0.15 mL of MEK. The mixture wassonicated for ˜1 min, following which precipitation was observed. Anadditional 0.075 mL of MEK was added and the mixture heated up to 75° C.The solvent was partially evaporated under nitrogen flow evaporated;0.05 mL of MEK added and the mixture seeded with ˜2 mg of crystalsobtained in B above. The solution was then stirred for ˜8 h at 75° C.and a solid recovered by filter centrifugation (0.2 μm PTFE, 1 min,15000 rpm). The material was dried overnight under vacuum at r.t. andthe solid product analyzed by PXRD (FIG. 18) FT Raman (FIG. 19) andshown to be

Polymorphic Form 3 of Compound 1.

Example 7—Thermodynamic Stability of Polymorphic Forms

A mixture with similar ratios of the products of Example 4, Experiment15 (Form 1), Example 4, Experiment 9 (form 2+x) and Example 4,Experiment 6 (Form 2+Form 3) were suspended in acetonitrile and shakenfor 13 days at 22° C. to give a product designated Product P24). Thesolid was recovered by filter centrifugation and characterized by PXRD.FIG. 16 shows the PXRD pattern of Product P24 compared with that of theproduct of Experiment P9 of Example 4. The two PXRD patterns areessentially the same although that of Product P9 shows a few additionalsignals. These signals could be assigned to (i) another crystalline formor (ii) the signals could not be detected for Product P24 because thediffractogram has a lower intensity.

Thus, after 13 days at 22° C. the PXRD corresponds to that of Form 2.Based on this result it can be deduced that Form 2 is the most stableform at room temperature.

Indexing of PXRD can be used to determine if a given pattern correspondsto a pure solid phase. The PXRD pattern of Product P24 (file: J893)could be successfully indexed, and the lattice was found to betriclinic. The resulting lattice parameters can be seen in Table 3. Thefinal fit between the observed and calculated diffraction patterns isshown in FIG. 17 and the low R-values (see Table 3) confirm the goodfit. This confirms that Form 2 corresponds to a true polymorphic formand not to a mixture of forms.

Product P9 of Example 4 could also be indexed within the same spacegroup and similar lattice parameters. However, some few signals ofproduct P9 could not be indexed. These signals could be assigned toanother crystalline form (maybe e.g. polymorph, impurity ordegradation).

TABLE 3 Lattice parameters and LeBail-Fit details for the laboratoryPXRD data for Form 2 obtained at room temperature. Sample Product P24file J893 a 10.8 ± 0.1 Å b 13.9 ± 0.1 Å c  7.8 ± 0.1 Å α 101. ± 1°   β110 ± 1°   γ 79 ± 1°   cell volume 1.068 Å³ RP 4.9% Weighted RP 7.1%

Example 8—Solubility of Polymorphic Forms

The solubility of Form 1, Form 2 and Form 3 was determined by HPLC infasted state simulated intestinal fluid (FaSSIF) and fed state simulatedintestinal fluid (FeSSIF) at 25° C. FaSSIF and FeSSIF were prepared fromSIF powder, available at PHARES, Switzerland. Suspensions of both formswere prepared and equilibrated for 24 hours at 25° C. The suspensionswere filtered. The pH values of the resulting saturated solutions weremeasured. The filtrates were diluted and analyzed by HPLC using ageneral, unoptimized method. The values listed below are averages overmultiple repetitions. Additionally Raman spectra of the recovered solidswere recorded.

TABLE 4 pH of Crystalline Solubility Saturated Form Solvent (mg/mL) FTRaman solution Form 2 FeSSIF 0.35 Agrees with Form 2 5.0 Form 1 FeSSIF1.18 Differences from Form 1 4.9 Form 3 FeSSIF 2.12 Agrees with Form 35.0 Form 2 FaSSIF 0.55 Agrees with Form 2 6.1 Form 1 FaSSIF 0.72 Agreeswith Form 1 5.7 Form 3 FaSSIF 1.31 Agrees with Form 3 5.4

The results set out in Table 4 show that Form 3 is more soluble in bothFaSSIF and FeSSIF. This increased solubility will make formulation ofForm 3 easier and it is possible that it may also to lead to increasedbioavailability for oral formulations of the compound.

The invention claimed is:
 1. A polymorphic form of[5-fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-aceticacid (Compound 1), characterised in that it gives an FT-Raman spectrumwhich is characterised by peaks at 3068±2 cm⁻¹, 3054±2 cm⁻¹, 2976±2cm⁻¹, 1582±2 cm⁻¹, 1427±2 cm⁻¹, 1298±2 cm⁻¹, 1213±2 cm⁻¹, 1190±2 cm⁻¹,1164±2 cm⁻¹, 1060±2 cm⁻¹, 956±2 cm⁻¹, 927±2 cm⁻¹, 834±2 cm⁻¹, 700±2cm⁻¹, 502±2 cm⁻¹, 421±2 cm⁻¹, 401±2 cm⁻¹, 388±2 cm⁻¹, 363±2 cm⁻¹, 353±2cm⁻¹, 301±2 cm⁻¹, 208±2 cm⁻¹, 116±2 cm⁻¹.
 2. The polymorphic form ofCompound 1 of claim 1 which comprises not more than 2% of other forms ofCompound
 1. 3. The polymorphic form of Compound 1 of claim 1 whichcomprises not more than 0.1% by weight of solvent.
 4. A process for thepreparation of the polymorphic form of Compound 1 of claim 1 comprising:(a). suspending [5-fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-acetic acid inmethylethylketone; (b). stirring the suspension at a temperature ofabout 15 to 25° C. for 15 to 30 days; and (c). isolating and drying thesolid[5-fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-aceticacid.
 5. The process of claim 4, further comprising: (d). dissolving theproduct of (c) in methyl ethyl ketone at an elevated temperature of fromabout 65 to 80° C. to obtain a saturated solution; (e). partiallyevaporating the solvent; (f). stirring the mixture for 20-36 hours suchthat crystallisation takes place; and (g). isolating the crystallineCompound
 1. 6. The process of claim 5, further comprising: (h).preparing a saturated solution of Compound 1 in methylethylketone at anelevated temperature of about 65-80° C.; (i). seeding the solution withthe crystalline product of (g); (j). allowing crystallisation to takeplace; and (k). isolating the crystalline product.
 7. The process ofclaim 6 comprising repeating (h) to (k) using the product of (k) as theseed crystals for (i).
 8. A method for the treatment of a CRTH2-mediateddisease or condition selected from the group consisting of asthma,asthma exacerbations, chronic obstructive pulmonary disease, allergicrhinitis conjunctivitis, nasal polyps, atopic dermatitis, contacthypersensitivity (including contact dermatitis), eosinophilic cough,eosinophilic bronchitis, eosinophilic gastroenteritis, eosinophilicesophagitis, food allergies, inflammatory bowel disease, ulcerativecolitis, Crohn's disease, mastocytosis, urticaria, hypereosinophilicsyndrome, hyper IgE syndrome, fibrotic diseases, Churg-Strauss syndrome,and multiple sclerosis, comprising administering to a patient in need ofsuch treatment an effective amount of the polymorphic form of Compound 1of claim
 1. 9. A method for the treatment of asthma exacerbationsinduced by respiratory syncytial virus or rhinovirus, comprisingadministering to a patient in need of such treatment an effective amountof the polymorphic form of Compound 1 of claim
 1. 10. A pharmaceuticalor veterinary composition comprising the polymorphic form of Compound 1of claim 1 and a pharmaceutically or veterinarily acceptable excipient.11. The composition of claim 10 further comprising one or moreadditional active agents useful in the treatment of diseases andconditions mediated by PGD₂ or other agonists at the CRTH2 receptor. 12.The composition of claim 11 wherein the additional active agent isselected from: other CRTH2 receptor antagonists; Suplatast tosylate andsimilar compounds; β2 adrenoreceptor agonists such as metaproterenol,isoproterenol, isoprenaline, albuterol, salbutamol, formoterol,salmeterol, indacaterol, terbutaline, orciprenaline, bitolterol mesylateand pirbuterol or methylxanthines such as theophylline andaminophylline, mast cell stabilisers such as sodium cromoglycate ormuscarinic receptor antagonists such as tiotropium; antihistamines, forexample histamine H₁ receptor antagonists such as loratadine,cetirizine, desloratadine, levocetirizine, fexofenadine, astemizole,azelastine and chlorpheniramine or H₄ receptor antagonists; α₁ and α₂adrenoreceptor agonists such as propylhexedrine phenylephrine,phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride,oxymetazoline hydrochloride, tetrahydrozoline hydrochloride,xylometazoline hydrochloride and ethylnorepinephrine hydrochloride;modulators of chemokine receptor function, for example CCR1, CCR2,CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11(for the C—C family) or CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for theC—X—C family) and CX₃CR1 for the C—X₃—C family; Leukotriene antagonistssuch as montelukast, pranlukast and zafirlukast leukotriene biosynthesisinhibitors such as 5-lipoxygenase inhibitors or 5-lipoxygenaseactivating protein (FLAP) inhibitors such as zileuton, ABT-761,fenleuton, tepoxalin, Abbott-79175,N-(5-substituted)-thiophene-2-alkylsolfonamides, 2,6-di-tert-butylphenolhydrazones, methoxytetrahydropyrans such as ZD2138, SB-210661,pyridinyl-substituted-2-cyanonaphthalene compounds such as L-739010,2-cyanoquinoline compounds such as L-746,530, indole and quinolinecompounds such as MK-591, MK-886 and BAY x 1005; Phosphdiesteraseinhibitors, including PDE4 inhibitors such as roflumilast; anti-IgEantibody therapies such as omalizumab; anti-infectives such as fusidicacid (particularly for the treatment of atopic dermatitis); anti-fungalssuch as clotrimazole (particularly for the treatment of atopicdermatitis); immunosuppressants such as tacrolimus and particularlypimecrolimus in the case of inflammatory skin disease or alternativelyFK-506, rapamycin, cyclosporine, azathioprine or methotrexate;Immunotherapy agents including allergen immunotherapy such as Grazax;corticosteroids such as prednisone, prednisolone, flunisolide,triamcinolone acetonide, beclomethasone dipropionate, budesonide,fluticasone propionate mometasone furoate and fluticasone furoate drugswhich promote Th1 cytokine response such as interferons, TNF or GM-CSF;other antagonists of PGD₂ acting at other receptors such as DPantagonists; drugs that modulate cytokine production such as inhibitorsof TNFα converting enzyme (TACE) anti-TNF monoclonal antibodies, TNFreceptor immunoglobulin molecules, inhibitors of other TNF isoforms,non-selective COX-1/COX-2 inhibitors such as piroxicam, diclofenac,propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofenand ibuprofen, fenamates such as mefanamic acid, indomethacin, sulindacand apazone, pyrazolones such as phenylbutazone, salicilates such asaspirin; COX-2 inhibitors such as meloxicam, celecoxib, fofecoxib,valdecoxib and etoricoxib, low dose methotrexate, lefunomide,ciclesonide, hydroxychloroquine, d-penicillamine, auranofin orparenteral or oral gold; drugs that modulate the activity of Th2cytokines IL-4 and IL-5 such as blocking monoclonal antibodies andsoluble receptors for Th2 cytokines; PPAR-γ agonists such asrosiglitazone; or with anti-RSV antibodies such as Synagis (palivizumab)and agents that may be used to treat rhinovirus infection in the futuree.g. interferon-alpha, interferon-beta or other interferons.
 13. A kitfor the treatment of a disease or condition mediated by the action ofPGD2 at the CRTH2 receptor comprising; (a) a first container comprisingthe polymorphic form of Compound 1; and (b) a second containercomprising an additional agent useful in the treatment of diseases orconditions mediated by PGD2 or other agonists at the CRTH2 receptor,wherein the additional active agent is selected from the agents listedin claim
 12. 14. The composition of claim 12 wherein the additionalactive agent is montelukast.
 15. A process for the preparation of thepharmaceutical or veterinary composition of claim 10, comprisingbringing into association the polymorphic form of Compound 1 and apharmaceutically or veterinarily acceptable excipient.
 16. A productcomprising the polymorphic form of Compound 1 and one or more of theagents listed in claim 12 as a combined preparation for simultaneous,separate, or sequential use in the treatment of a disease or conditionmediated by the action of PGD₂ at the CRTH2 receptor.